Bottom Line:
Here, we show that adoptively transferred or thymically derived OT-I cells activated by cross-presentation are deleted from the peripheral pool of recirculating lymphocytes.Such deletion only required antigen recognition on a bone marrow-derived population, suggesting that cells of the professional APC class may be tolerogenic under these circumstances.Our results provide a mechanism by which the immune system can induce CD8(+) T cell tolerance to autoantigens that are expressed outside the recirculation pathway of naive T cells.

ABSTRACTIn this report, we show that cross-presentation of self-antigens can lead to the peripheral deletion of autoreactive CD8(+) T cells. We had previously shown that transfer of ovalbumin (OVA)-specific CD8(+) T cells (OT-I cells) into rat insulin promoter-membrane-bound form of OVA transgenic mice, which express the model autoantigen OVA in the proximal tubular cells of the kidneys, the beta cells of the pancreas, the thymus, and the testis of male mice, led to the activation of OT-I cells in the draining lymph nodes. This was due to class I-restricted cross-presentation of exogenous OVA on a bone marrow-derived antigen presenting cell (APC) population. Here, we show that adoptively transferred or thymically derived OT-I cells activated by cross-presentation are deleted from the peripheral pool of recirculating lymphocytes. Such deletion only required antigen recognition on a bone marrow-derived population, suggesting that cells of the professional APC class may be tolerogenic under these circumstances. Our results provide a mechanism by which the immune system can induce CD8(+) T cell tolerance to autoantigens that are expressed outside the recirculation pathway of naive T cells.

Figure 4: Peripheral deletion of OT-I cells that mature in the thymus of TG-RIP mice. Thymus grafts from TG-littermate mice (A and B) and TG-RIP mice (D and E) were analyzed for CD4+, CD8+, and Vα2+ cells by flow cytometry 16 wk after bone marrow reconstitution. Expression of Vα2 by CD4−CD8+ cells is shown in the histograms B and E. LN cells of the same transgenic (C) and nontransgenic (F) mice were stained for CD8+ and Vα2+ expression. The same staining conditions for Vα2 were used for thymus and LN cells. The data shown here is representative for eight pairs of manipulated mice investigated.

Mentions:
In contrast with the RIP–mOVA mice given large numbers of OT-I cells, which became diabetic within 9 d, only 1 of 12 TG-RIP mice developed the disease when followed for >116 d. Analysis of the thymus grafts 4 mo after implantation showed that OT-I cells (CD8+CD4−Vα2+ cells) were able to mature in TG-RIP mice (Fig. 4). The proportion of mature OT-I cells in the thymus was equivalent to that of nontransgenic controls (Fig. 4, A and D), supporting the view that the thymic deletion reported earlier for the double-transgenic mice (27) was the result of aberrant thymic expression of mOVA.

Figure 4: Peripheral deletion of OT-I cells that mature in the thymus of TG-RIP mice. Thymus grafts from TG-littermate mice (A and B) and TG-RIP mice (D and E) were analyzed for CD4+, CD8+, and Vα2+ cells by flow cytometry 16 wk after bone marrow reconstitution. Expression of Vα2 by CD4−CD8+ cells is shown in the histograms B and E. LN cells of the same transgenic (C) and nontransgenic (F) mice were stained for CD8+ and Vα2+ expression. The same staining conditions for Vα2 were used for thymus and LN cells. The data shown here is representative for eight pairs of manipulated mice investigated.

Mentions:
In contrast with the RIP–mOVA mice given large numbers of OT-I cells, which became diabetic within 9 d, only 1 of 12 TG-RIP mice developed the disease when followed for >116 d. Analysis of the thymus grafts 4 mo after implantation showed that OT-I cells (CD8+CD4−Vα2+ cells) were able to mature in TG-RIP mice (Fig. 4). The proportion of mature OT-I cells in the thymus was equivalent to that of nontransgenic controls (Fig. 4, A and D), supporting the view that the thymic deletion reported earlier for the double-transgenic mice (27) was the result of aberrant thymic expression of mOVA.

Bottom Line:
Here, we show that adoptively transferred or thymically derived OT-I cells activated by cross-presentation are deleted from the peripheral pool of recirculating lymphocytes.Such deletion only required antigen recognition on a bone marrow-derived population, suggesting that cells of the professional APC class may be tolerogenic under these circumstances.Our results provide a mechanism by which the immune system can induce CD8(+) T cell tolerance to autoantigens that are expressed outside the recirculation pathway of naive T cells.

ABSTRACTIn this report, we show that cross-presentation of self-antigens can lead to the peripheral deletion of autoreactive CD8(+) T cells. We had previously shown that transfer of ovalbumin (OVA)-specific CD8(+) T cells (OT-I cells) into rat insulin promoter-membrane-bound form of OVA transgenic mice, which express the model autoantigen OVA in the proximal tubular cells of the kidneys, the beta cells of the pancreas, the thymus, and the testis of male mice, led to the activation of OT-I cells in the draining lymph nodes. This was due to class I-restricted cross-presentation of exogenous OVA on a bone marrow-derived antigen presenting cell (APC) population. Here, we show that adoptively transferred or thymically derived OT-I cells activated by cross-presentation are deleted from the peripheral pool of recirculating lymphocytes. Such deletion only required antigen recognition on a bone marrow-derived population, suggesting that cells of the professional APC class may be tolerogenic under these circumstances. Our results provide a mechanism by which the immune system can induce CD8(+) T cell tolerance to autoantigens that are expressed outside the recirculation pathway of naive T cells.